combination for the treatment of osteoarthritis

ABSTRACT

The present invention relates to the use of a combination of glycine, proline, and optionally a natural or synthetic viscosity-controlling polymer, and/or lysine and/or leucine, to prepare a composition for the treatment of osteoarthritis.

The present invention relates to a combination of glycine, proline, andoptionally a natural or synthetic viscosity-controlling polymer, and/orlysine and/or leucine, for the treatment of osteoarthritis, inparticular for patellofemoral or femorotibial osteoarthritis of theknee, osteoarthritis of the hip and osteoarthritis of the shoulder.

TECHNICAL BACKGROUND

Osteoarthritis is the most common joint disease among the rheumaticdisorders affecting the Western world. It is a chronic degenerativejoint disease which may be diffuse or localised, affecting the cartilageof the diarthrodial joints, where the normal metabolic process of thechondrocytes is impaired, leading to softening, fibrillation, ulcerationand subsequent sclerosis of the subchondral bone, and in the finalstages to new bone formation and subchondral cysts.

Osteoarthritis, which mainly affects women, most frequently involves thepatellofemoral joint, the femorotibial joint, the hip and the shoulder.Osteoarthritis of the knee, or gonarthritis, is particularly frequentand disabling. The clinical picture is initially dominated bycharacteristically mechanical pain at the anterior or anteromedial site,which is attenuated by rest. After lengthy inactivity, for example inthe mornings or after sitting for a long time, painful post-inactivityspasms may be experienced. However, they are shortlived, and attenuatedby walking. Pain may be triggered by using stairs, especially walkingdownstairs, squatting, especially in the case of patellofemoralosteoarthritis, or lengthy use of vehicle pedals. Initially there mayalso be pain in the periarticular areas, and modest effusion. The painmay later affect the whole joint, become nocturnal, and be accompaniedby frequent joint effusions. Functional impairment only appears at alate stage, despite the presence of a considerable valgus or varusmalalignment.

Until a few years ago the main therapeutic objective of the treatment ofknee osteoarthritis was controlling the symptoms (pain and functionallimitation), traditionally achieved with NSAIDs (non-steroidalanti-inflammatory drugs) and other painkillers.

The ideal treatment of knee osteoarthritis requires a combination ofpharmacological and other treatments, which must be tailored to thepatient's requirements on the basis of local risk factors (obesity,mechanical factors, physical activity), general risk factors (age,comorbidity, multiple drug therapy), pain intensity levels and degree ofdisability, signs of inflammation (effusion), location and degree ofstructural damage.

Non-pharmacological treatment of knee osteoarthritis should includerehabilitation programmes, physical exercise, the use of aids (walkingsticks, insoles or knee braces) and weight loss, where necessary.

The first-line medicament for the treatment of pain in kneeosteoarthritis is paracetamol, which is used at doses lower than orequal to 3 gm/day in addition to other osteoarthritis drugs.

Topical applications of NSAIDs or capsaicin can be a useful treatment ifused for short periods, especially for patients who refuse or are unableto take oral medicaments.

NSAIDs are considered for patients who fail to respond to paracetamoland patients at gastrointestinal risk; in that case, conventional COXIBsor NSAIDs associated with proton pump inhibitors are used.

Opioid analgesics represent useful alternatives in patients for whomNSAIDs or COXIBs are contraindicated because they are ineffective orpoorly tolerated.

Other drugs used are those which, when administered by the oral orintra-articular route, reduce the clinical symptoms at varying rates, bydifferent methods from analgesics or NSAIDs. This group consists of twodifferent categories: slow-acting symptomatic medicaments forosteoarthritis, and medicaments able to modify the progress ofosteoarthritis. Glucosamine sulphate, chondroitin sulphate, soya andavocado extracts, diacerein, hyaluronic acid and S-adenosylmethioninebelong to the first group. These medicaments have a direct action on thechondrocytes and synoviocytes and consequently have beneficial effectson the cartilage structure. Their efficacy against the symptoms startsslowly (1-2 weeks) but lasts for a long time: up to two months afterdiscontinuance of the treatment.

Intra-articular injection of cortisones with a long-lasting action isindicated for acute joint pain, especially if it is associated withintra-articular effusions.

Research currently focuses on molecules with specific effects on thepathogenetic mechanisms of osteoarthritis, modifying both the symptomsand the joint structure to counteract the progress of the disease.

International patent application PCT/EP2006/009966 describeswound-healing pharmaceutical compositions comprising a combination ofglycine, lysine, leucine and proline and sodium hyaluronan, which isparticularly effective in facilitating the cell renewal process thatforms the basis of rapid wound-healing, promoting connective tissuereconstruction and consequent regeneration of the epithelial cells.

DESCRIPTION OF THE INVENTION

It has now been found that the use of intra-articular compositionscomprising glycine, proline, and optionally a natural or syntheticviscosity-controlling polymer, lysine and/or leucine, is effective inthe treatment of osteoarthritis, especially as regards the aspect ofpain management.

The compositions according to the invention have a significant effect onpain reduction and improvement in the joint function, and consequentlyon the patient's quality of life. This effect is long-lasting, evenafter the treatment is discontinued (up to two months).

The use of the compositions according to the invention thereforeprovides a useful treatment for osteoarthritis, especially in painmanagement, offering fast, effective pain reduction.

The present invention therefore relates to a combination comprising:

a) glycine,

b) proline,

and optionally

c) a natural or synthetic viscosity-controlling polymer, and/or

d) lysine, and/or

e) leucine,

for intra-articular administration for the treatment of osteoarthritis,in particular knee osteoarthritis.

According to the invention, the natural or syntheticviscosity-controlling polymer is selected from hyaluronic acid or a saltthereof, polyvinylpyrrolidone, and cellulose derivatives.

According to a preferred aspect, the natural or syntheticviscosity-controlling polymer is hyaluronic acid or a salt thereof.

According to the invention, the aminoacids are present in the L form.

According to a preferred aspect, the intra-articular compositionsaccording to the invention will contain the various active constituentsin the following composition ranges by weight:

a) 25 to 500 mg of glycine,

b) 40 to 300 mg of proline,

and optionally

c) 5 to 50 mg of hyaluronic acid or a salt thereof, and/or

d) 5 to 100 mg of lysine, and/or

e) 5 to 50 mg of leucine.

The compositions according to the invention are formulated suitably forintra-articular administration in the form of reconstitutable powders,solutions and the like, and will be prepared according to conventionalmethods well known in pharmaceutical technology, such as those describedin Remington's Pharmaceutical Handbook, Mack Publishing Co., N.Y., USA,using excipients suitable for their final use.

Pharmacological Tests

The purpose of the trial was to evaluate the therapeutic efficacy ofintra-articular administration of a composition according to theinvention in patients suffering from primary osteoarthritis of the kneeby assessing the thickness of the cartilage, the intensity of pain andthe patients' quality of life before and after treatment.

The composition according to the invention used for the trial consistedof 2 bottles: bottle A, containing sodium hyaluronan in aqueoussolution; and bottle B, containing a freeze-dried powder based onglycine (182 mg), L-proline (150 mg), L-lysine (35 mg) and L-leucine (21mg). Before administration, the product must be reconstituted (thefreeze-dried powder in bottle B is dissolved in the solution containedin bottle A) to provide a transparent solution containing no particulatematter.

The area to be treated was disinfected, and then anaesthetised with ananaesthetic cream to be applied 30 minutes before the operation. Theinfiltrations were repeated once a week for 5 weeks.

No overdoses or interactions with other medicaments are known. Rarely,local reactions due to hypersensitisation may occur, manifested byoedema, a sensation of warmth and/or itching.

11 patients suffering from knee osteoarthritis (7 men aged between 50and 80 years and 9 women aged between 51 and 72 years) were examined.The staging of the degree of osteoarthritis was performed according tothe Kellgren and Lawrence score (Kellgren J H, Lawrence J S.Radiological assessment of osteo-arthrosis. Ann Rhem Dis 1957; 16:494-502).

The Inclusion Criteria were:

1) Diagnosis of knee osteoarthritis according to the ACR (AmericanCollege of Rheumatology) diagnostic criteria

-   -   knee pain associated with at least three of the following        criteria:

a—age over 50 years

b—stiffness after resting for less than thirty minutes

c—creaking

d—bone pain

e—enlargement of bone contour, not warm on palpation

2) Radiological stage of disease between I and II on the Kellgren andLawrence scale.

I: doubtful reduction in joint space and possible formation ofosteophytes,

II: well-defined osteophytes, and possible reduction in joint space,

III: multiple osteophytes and well-defined reduction in joint space,sclerosis and possible deformity of bone contour,

IV: large osteophytes, marked reduction in joint space, severe sclerosisand well-defined deformity of bone contour.

The whole population examined presented radiological stage II of thedisease apart from one woman, with stage I.

On entry to the trial, and after 3 and 6 months, a case history wastaken with collection of personal and anthropometric data (height,weight, body mass index (BMI), blood pressure and heart rate), and thefollowing parameters were evaluated:

Intensity of pain on a visual analogue scale (VAS), expressed inmillimetres from 0 (normal) to 100 (maximum intensity of pain),performed by both the doctor and the patient;

Severity of disease using the Womac (Western Ontario and McMasterUniversities) Osteoarthritis Index questionnaire, a scale ofself-assessment of knee osteoarthritis, consisting of 24 items used tomonitor the progress of the disorder and determine the efficacy of thetreatment.

Thickness of knee joint cartilage in the central, medial and lateralcompartment by means of an ultrasound scan (performed with a PhilipsEnvisor 250 ultrasound system with multifrequency linear probe from 5 to13 MHz).

Results

The composition according to the invention was well tolerated, with nolocal or systemic allergic reactions. The results of the clinicalevaluation are set out in Tables I and II.

The data relating to evaluation of pain intensity and the severity ofthe disease are set out in Table I below.

a) Pain Intensity Assessment

The mean pain value (VAS) evaluated by patients at the beginning of thetrial was 58.03 (±8.31); after three months, the mean value was 28.07(±8.55), a percentage decrease of 58% (p<0.05); and after six months themean value had fallen to 16.20 (±9.28) (p<0.05). The mean pain value(VAS) evaluated by the doctors at the beginning of the trial was 56.18(±9.66); after three months, the mean value was 22.03 (±7.32), apercentage decrease of 54% (p<: 0.05); after six months the mean valuehad fallen still further, to 9.11 mm (±6.97), a percentage decrease of71% compared with baseline (p<0.05).

b) Assessment of Severity of Disease

At the beginning of the trial the mean WOMAC value was 55.03 (±27.04);after three months the mean value had fallen to 24.00 (±25.44), apercentage decrease of 65% (p<0.001); and after six months the meanvalue had further decreased to 11.99 mm (±10.86), a percentage decreaseof 83% compared with baseline (p<0.001).

TABLE I Clinical evaluation of patients examined at the beginning of thetrial (baseline), and 3 and 6 months after the infiltration treatmentCLINICAL EVALUATION 3 months 6 months comparison vs. comparison vs.baseline baseline baseline patient VAS 58.03 (±8.31) 28.07 (±8.55) 16.20(±9.28) mean (SE) (29-97) (6-63) (4-67) (range) p < 0.05* p < 0.05*doctor VAS 56.18 (±9.66) 22.03 (±7.32)  9.11 (±6.97) mean (SE) (15-88)(2-45) (3-42) (range) p < 0.05* p < 0.05* (range) WOMAC 55.03 ± 27.0424.00 ± 25.44 11.99 ± 10.86 mean ± SD (18-89) (4-68) (4-31) (range) p <0.001° p < 0.001° *Wilcoxon test for paired data: t-test for paired data

The data relating to the percentage decreases in the clinicalevaluations of the patients examined 3 and 6 months after theinfiltration treatment are set out in Table II below.

TABLE II Clinical evaluation of percentage decreases in clinicalevaluations 3 and 6 months after infiltration treatment CLINICALEVALUATION % decreases % decreases after 3 months after 6 months patientVAS 58 ± 27 75 ± 22 mean ± SD (11-93) (43-97) (range) doctor VAS 54 ± 1671 ± 27 mean ± SD (40-84) (42-91) (range) WOMAC 65 ± 29 83 ± 11 mean ±SD (13-92) (65-93) (range)

c) Thickness of Joint Cartilage

The ultrasound evaluation of the cartilage (presented in Table III)shows that the mean thickness of the medial cartilage at baseline was0.13 mm (±0.07); after 3 months that thickness had increased to 0.14 mm(±0.08), a percentage increase of 6.5% (p=n/s); after six months it hasfurther increased to 0.15 mm (±0.08), a percentage increase of 14.1%compared with baseline (p<0.05).

The mean thickness of the lateral cartilage at baseline was 0.18 (±0.06)mm; after 3 months it had increased to 0.19 (±0.07) mm, a percentagegrowth of 2.9% (p=n/s); after six months the mean value showed astatistically significant increase compared with baseline.

The mean thickness of the central cartilage after three months (0.29mm±0.07) was not significant, whereas after six months (0.31±0.11 mm)there was a statistically significant increase compared with thebaseline value.

TABLE III Mean thickness of joint cartilage at the beginning of thetrial (baseline), and 3 and 6 months after infiltration treatmentTHICKNESS OF JOINT CARTILAGE 3 months 6 months comparison vs. comparisonvs. baseline baseline baseline MEDIAL [mm] 0.13 ± 0.07 0.14 ± 0.08 0.15± 0.08 mean ± SD (0.09-0.25) (0.08-0.26) (0.10-0.27) (range) p n.s. p <0.05 LATERAL [mm] 0.18 ± 0.06 0.19 ± 0.07 0.21 ± 0.09 mean ± SD(0.07-0.31) (0.10-0.32) (0.10-0.32) (range) p n.s. p < 0.05 CENTRAL [mm]0.28 ± 0.05 0.29 ± 0.07 0.31 ± 0.11 mean ± SD (0.11-0.43) (0.14-0.44)(0.14-0.45) (range) p n.s. p < 0.05

Analysis of the results set out above demonstrates a definiteimprovement in clinical symptoms after administration of the compositionaccording to the invention. Said improvement, which was present afteronly 3 months, was maintained after 6 months, when a further benefit onthe osteoarticular symptoms was observed. The VAS pain values after 3and 6 months had significantly declined compared with baseline,demonstrating that the medicament does not merely increase theviscoelasticity of the synovial fluid, but also has a favourable effecton the pain symptom, and consequently on the patient's quality of life.

1. An intra-articular formulation for the treatment of osteoarthritiscomprising: a) glycine, b) proline, and optionally c) a natural orsynthetic viscosity-controlling polymer, and/or d) lysine, and/or e)leucine.
 2. The formulation as claimed in claim 1, whereinosteoarthritis is patellofemoral or femorotibial knee osteoarthritis,hip osteoarthritis and shoulder osteoarthritis.
 3. The formulation asclaimed in claim 1, wherein the natural or syntheticviscosity-controlling polymer is selected from hyaluronic acid or a saltthereof, polyvinylpyrrolidone and cellulose derivatives.
 4. Theformulation as claimed in claim 3, wherein the natural or syntheticviscosity-controlling polymer is hyaluronic acid or a salt thereof. 5.The formulation as claimed in claim 1, wherein the amino acids are in Lform.
 6. The formulation as claimed in claim 1, wherein the variouscomponents of the combination are present in the following ranges byweight: a) 25 to 500 mg of glycine, b) 40 to 300 mg of proline, andoptionally c) 5 to 50 mg of hyaluronic acid or a salt thereof, and/or d)5 to 100 mg of lysine, and/or e) 5 to 50 mg of leucine.
 7. Theformulation as claimed in claim 1, in the form of powders forreconstitution or viscous solutions in biocompatible solvents.